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TCR Peptide Therapy in Human Autoimmune Diseases

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Abstract

Inflammatory Th1 cells reacting to tissue/myelin derived antigens likely contribute to the pathogenesis of diseases such as multiple sclerosis (MS), rheumatoid arthritis (RA), and psoriasis. One regulatory mechanism that may be useful for treating autoimmune diseases involves an innate second set of Th2 cells specific for portions of the T cell receptor of clonally expanded pathogenic Th1 cells. These Th2 cells are programmed to respond to internally modified V region peptides from the T cell receptor (TCR) that are expressed on the Th1 cell surface in association with major histocompatibility molecules. Once the regulatory Th2 cells are specifically activated, they may inhibit inflammatory Th1 cells through a non-specific bystander mechanism. A variety of strategies have been used by us to identify candidate disease-associated TCR V genes present on pathogenic Th1 cells, including BV5S2, BV6S5, and BV13S1 in MS, BV3, BV14, and BV17 in RA, and BV3 and BV13S1 in psoriasis. TCR peptides corresponding to the mid region of these BV genes were found to be consistently immunogenic in vivo when administered either i.d. in saline or i.m. in incomplete Freund's adjuvant (IFA). In MS patients, repeated injection of low doses of peptides (100-300 μg) significantly boosted the number of TCR-reactive Th2 cells. These activated cells secreted cytokines, including IL-10, that are known to inhibit inflammatory Th1 cells. Cytokine release could also be induced in TCR-reactive Th2 cells by direct cell-cell contact with Th1 cells expressing the target V gene. These findings indicate the potential of regulatory Th2 cells to inhibit not only the target Th1 cells, but also bystander Th1 cells expressing different V genes specific for other autoantigens. TCR peptide vaccines have been used in our studies to treat a total of 171 MS patients (6 trials), 484 RA patients (7 trials), and 177 psoriasis patients (2 trials). Based on this experience in 824 patients with autoimmune diseases, TCR peptide vaccination is safe and well tolerated, and can produce significant clinical improvement in a subset of patients that respond to immunization. TCR peptide vaccination represents a promising approach that is well-suited for treating complex autoimmune diseases.

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REFERENCES

  1. Vandenbark, A. A., Hashim, G. A., and Offner, H. 1996. T cell receptor peptides in treatment of autoimmune disease: rationale and potential. J. Neurosci. Res. 43:391–402.

    Google Scholar 

  2. Toyonaga, B. and Mak, T. W. 1987. Genes of the T-cell antigen receptor in normal and malignant T cells. Ann. Rev. Immunol. 585–620.

  3. Davis, M. M. and Bjorkman, P. J. 1988. T-cell antigen receptor genes and T-cell recognition. Nature 334:395–402.

    Google Scholar 

  4. Cohen, I. R. and Young, D. B. 1991. Autoimmunity, microbial immunity and the immunological homunculus. Immunology Today 12:105–110.

    Google Scholar 

  5. Vandenbark, A. A., Hashim, G., and Offner, H. 1989. Immunization with a synthetic T-cell receptor V-region peptide protects against experimental autoimmune encephalomyelitis. Nature 341:541–544.

    Google Scholar 

  6. Howell, M. D., Winters, S. T., Olee, T., Powell, H. C., Carlo, D. J., and Brostoff, S. W. 1989. Vaccination against experimental allergic encephalomyelitis with T cell receptor peptides. Science 246:668–670.

    Google Scholar 

  7. Jiang, H., Sercarz, E., Nitecki, D., and Pernis, B. 1991. The problem of presentation of T cell receptor peptides by activated T cells. Ann. NY Acad. Sci. 636:28–32.

    Google Scholar 

  8. Vandenbark, A. A., Chou, Y. K., Whitham, R., Mass, M., Buenafe, A., Liefeld, D., Kavanagh, D., Cooper, S., Hashim, G. A., Offner, H., and Bourdette, D. N. 1996. Treatment of multiple sclerosis with T cell receptor peptides: Results of a double-blind pilot trial. Nature Med. 2:1109–1115.

    Google Scholar 

  9. Chou, Y. K., Weinberg, A. D., Buenafe, A., Bourdette, D. N., Whitham, R., Kaleeba, J. A. R., Robey, I. F., Kavanagh, D. G., Offner, H., and Vandenbark, A. A. 1996. MHC-restriction, cytokine profile, and immunoregulatory effects of human T cells specific for TCR VB CDR2 peptides: Comparison with myelin basic protein-specific T cells. J. Neurosci. Res. 45:838–851.

    Google Scholar 

  10. Zipp, F., Kerschensteiner, M., Dornmair, K., Malotka, J., Schmidt, S., Bender, A., Giegerich, G., deWaal-Malefyt, R., Wekerle, H., and Hohlfeld, R. 1998. Diversity of the anti-T-cell receptor immune response and its implications for T-cell vaccination therapy of multiple sclerosis. Brain 121:1391–1393.

    Google Scholar 

  11. Saruhan-Direskeneli, G., Weber, F., Meinl, E., Pette, M., Giegerich, G., Hinkkanen, A., Epplen, J. T., Hohlfeld, R., and Wekerle, H. 1993. Human T cell autoimmunity against myelin basic protein: CD4+ cells recognizing epitopes of the T cell receptor B chain from a myelin basic protein-specific T cell clone. Eur. J. Immunol. 23:530–536.

    Google Scholar 

  12. Chou, Y. K., Morrison, W. J., Weinberg, A. D., Whitham, R., Bourdette, D. N., Hashim, G., Offner, H., and Vandenbark, A. A. 1994. Immunity to T cell receptor peptides in multiple sclerosis. II. T cell recognition of Vß5.2 and Vß6.1 CDR2 peptides. J. Immunol. 152:2520–2529.

    Google Scholar 

  13. Fiorentino, D. F., Zlotnik, A., Vieira, P., Mosmann, T. R., Howard, M., Moore, K. W., and O'Garra, A. 1991. IL-10 acts on the antigen-presenting cell to inhibit cytokine production by Th1 cells. J. Immunol. 146:3444–3451.

    Google Scholar 

  14. Rott, O., Fleischer, B., and Cash, E. 1994. Interleukin-10 prevents experimental allergic encephalomyelitis in rats. Eur. J. Immunol. 24:1434–1440.

    Google Scholar 

  15. Cua, D. J., Groux, H., Hinton, D. R., Stohlman, S. A., and Coffman, R. L. 1999. Transgenic interleukin 10 prevents induction of experimental autoimmune encephalomyelitis. J. Exp. Med. 189:1005–1010.

    Google Scholar 

  16. Vandenbark, A. A., Chou, Y. K., Bourdette, D. N., Whitham, R., and Offner, H. 1997. Therapeutic application of T cell receptor peptides. Drug News Persp. 10:341–346.

    Google Scholar 

  17. Sun, D., Qin, Y., Chluba, J., Epplen, J. T., and Wekerle, H. 1988. Suppression of experimentally induced autoimmune encephalomyelitis by cytolytic T-T cell interactions. Nature 332:843–846.

    Google Scholar 

  18. Kohrober, A., Schirmbeck, R., and Reimann, J. 1994. Vaccination with T cell receptor peptides primes anti-receptor cytotoxic T lymphocytes (CTL) and anergizes T cells specifically recognized by these CTL. Eur. J. Immunol. 24:1172–1180.

    Google Scholar 

  19. Zhang, J., Medaer, R., Stinissen, P., Hafler, D. A., and Raus, J. C. M. 1993. MHC-restricted depletion of human myelin basic protein-reactive T cells by T cell vaccination. Science 261:1451–1454.

    Google Scholar 

  20. Stinissen, P., Hermans, G., Hellings, N., and Raus, J. 1998. Functional characterization of CD8 anti-clonotypic T cells from MS patients treated with T cell vaccination. J. Neuroimmunol. 90:A564.

    Google Scholar 

  21. Ware, R., Jiang, H., Braunstein, N., Kent, J., Wiener, E., Pernis, B., and Chess, L. 1995. Human CD8+ T lymphocyte clones specific for T cell receptor Vß families expressed on autologous CD4+ T cells. Immunity 2:177–183.

    Google Scholar 

  22. Araga, S., LeBoeuf, R. D., and Blalock, J. E. 1993. Prevention of experimental autoimmune myasthenia gravis by manipulation of the immune network with a complementary peptide for the acetylcholine receptor. Proc. Natl. Acad. Sci. USA 90:8747–8751.

    Google Scholar 

  23. Vandenbark, A. A., Culbertson, N., Finn, T., Barnes, D., Buenafe, A., Burrows, G. G., Law, S., Chou, Y. K., and Offner, H. 2000. Human TCR as antigen: Homologies and potentially cross-reactive HLA-DR2-restricted epitopes within the AV and BV CDR2 loops. Crit. Rev. Immunol. 20:57–83.

    Google Scholar 

  24. Kotzin, B. L., Karuturi, S., Chou, Y. K., Lafferty, J., Forrester, J. M., Better, M., Nedwin, G. E., Offner, H., and Vandenbark, A. A. 1991. Preferential T cell receptor ß-chain variable gene use in myelin basic protein-reactive T cell clones from patients with multiple sclerosis. Proc. Natl. Acad. Sci. USA 88:9161–9165.

    Google Scholar 

  25. Offner, H. and Vandenbark, A. A. 1999. T cell receptor V genes in multiple sclerosis: Increased use of TCRAV8 and TCRBV5 in MBP-specific clones. Intern. Rev. Immunol. 18:9–36.

    Google Scholar 

  26. Raine, C. S. and Scheinberg, L. C. 1988. On the immunopathology of plaque development and repair in multiple sclerosis. J. Neuroimmunol. 20:189–194.

    Google Scholar 

  27. Olsson, T., Wang, W. Z., Hojeberg, B., Kostulas, V., Yu-Ping, J., Anderson, G., Ekre, H.-P., and Link, H. 1990. Autoreactive T lymphocytes in multiple sclerosis determined by antigeninduced secretion of interferon-gamma. J. Clin. Invest. 86:981–985.

    Google Scholar 

  28. Sun, J. B., Olsson, T., Wang, W. Z., Xiao, B. G., Kostulas, V., Fredrikson, S., Ekre, H. P., and Link, H. 1991. Autoreactive T and B cells responding to myelin proteolipid protein in multiple sclerosis and controls. Eur. J. Immunol. 21:1461–1468.

    Google Scholar 

  29. Chou, Y. K., Bourdette, D. N., Offner, H., Whitham, R., Wang, R., Hashim, G. A., and Vandenbark, A. A. 1992. Frequency of T cells specific for myelin basic protein and myelin proteolipid protein in blood and cerebrospinal fluid in multiple sclerosis. J. Neuroimmunol. 38:105–114.

    Google Scholar 

  30. Ota, K., Matsui, M., Milford, E. L., Macklin, G. A., Weiner, H. L., and Hafler, D. A. 1990. T cell recognition of an immunodominant myelin basic protein epitope in multiple sclerosis. Nature 346:183–185.

    Google Scholar 

  31. Trotter, J. L., Pelfrey, C. M., Trotter, A. L., Selvidge, J. A., Gushleff, K. C., Mohanakumar, T., and McFarland, H. F. 1998. T cell recognition of myelin proteolipid protein and myelin proteolipid protein peptides in the peripheral blood of multiple sclerosis and control subjects. J. Neuroimmunol. 84:172–178.

    Google Scholar 

  32. Noort, J. M., Sechel, A. C., Bajramovic, J. J., Ouagmiri, M. E., Polman, C. H., Lassmann, H., and Ravid, R. 1995. The small heat-shock protein a-B-crystallin as candidate autoantigen in multiple sclerosis. Nature 375:798–801.

    Google Scholar 

  33. Rosbo, N. K., Milo, R., Lees, M. B., Burger, D., Bernard, C. C., and Ben-Nun, A. 1993. Reactivity to myelin antigens in multiple sclerosis. Peripheral blood lymphocytes respond predominantly to myelin oligodendrocyte glycoprotein. J. Clin. Invest. 92:2602–2608.

    Google Scholar 

  34. Bieganowska, K. D., Ausubel, L. J., Modabber, Y., Slovik, E., Messersmith, W., and Hafler, D. A. 1997. Direct ex vivo analysis of activated fas-sensitive autoreactive T cells in human autoimmune disease. J. Exp. Med. 185:1585–1594.

    Google Scholar 

  35. Zhang, J., Markovic-Plese, S., Lacet, B., Raus, J., Weiner, H. L., and Hafler, D. A. 1994. Increased frequency of interleukin 2-responsive T cells specific for myelin basic protein and proteolipid protein in peripheral blood and cerebrospinal fluid of patients with multiple sclerosis. J. Exp. Med. 179:973–984.

    Google Scholar 

  36. Wilson, D. B., Golding, A. B., Smith, R. A., Dafashy, T., Nelson, J., Smith, L., Carlo, D. J., Brostoff, S. W., and Gold, D. P. 1997. Results of a phase I clinical trial of a T-cell receptor peptide vaccine in patients with multiple sclerosis. I. Analysis of T-cell receptor utilization in CSF cell populations. J. Neuroimmunol. 76:15–28.

    Google Scholar 

  37. Allegretta, M., Nicklas, J. A., Sriram, S., and Albertini, R. J. 1990. T cells responsive to myelin basic protein in patients with multiple sclerosis. Science 247:718–721.

    Google Scholar 

  38. Lodge, P. A., Johnson, C., and Sriram, S. 1996. Frequency of MBP and MBP peptide-reactive T cells in the HPRT mutant Tcell population of MS patients. Neurology 46:1410–1415.

    Google Scholar 

  39. Trotter, J. L., Damico, C. A., Cross, A. H., Pelfrey, C. M., Karr, R. W., Fu, X. T., and McFarland, H. F. 1997. HPRT mutant T-cell lines from multiple sclerosis patients recognize myelin proteolipid protein peptides. J. Neuroimmunol. 75:95–103.

    Google Scholar 

  40. Vandenbark, A. A., Bourdette, D. N., Whitham, R., Chou, Y. K., and Offner, H. 1993. Episodic changes in T cell frequencies to myelin basic protein in patients with multiple sclerosis. Neurology 43:2416–2417.

    Google Scholar 

  41. Weiner, H. L., Mackin, G. A., Matsui, M., Orav, E. J., Khoury, S. J., Dawson, D. M., and Hafler, D. A. 1993. Double-blind pilot trial of oral tolerization with myelin antigens in multiple sclerosis. Science 259:1321–1324.

    Google Scholar 

  42. Bielokova, B., Goodwin, B., Richert, N., Cortese, I., Kondo, T., Afshar, G., Gran, B., Eaton, J., Antel, J., Frank, J. A., McFarland, H. F., and Martin, R. 2000. Encephalitogenic potential of the myelin basic protein peptide (amino acids 83–99) in multiple sclerosis: Results of a phase II clinical trial with an altered peptide ligand. Nature Med. 6:1167–1175.

    Google Scholar 

  43. Zamvil, S. S., Nelson, P., Trotter, J., Mitchell, D., Knobler, R., Fritz, R., and Steinman, L. 1985. T-cell clones specific for myelin basic protein induce chronic relapsing paralysis and demyelination. Nature 317:355–358.

    Google Scholar 

  44. Mokhtarian, F., McFarlin, D. E., and Raine, C. S. 1984. Adoptive transfer of myelin basic protein-sensitized T cells produces chronic relapsing demyelinating disease in mice. Nature 309:356–358.

    Google Scholar 

  45. Alvord, J. E. C. 1984. Species-restricted encephalitogenic determinants. Pages 523–537, in Alvord, J. E. C., Kies, M. W., and Suckling, A. J. (eds.), Experimental Allergic Encephalomyelitis: A Useful Model for Multiple Sclerosis, Alan R. Liss, Inc., New York.

    Google Scholar 

  46. Ben-Nun, A. and Cohen, I. R. 1982. Experimental autoimmune encephalomyelitis (EAE) mediated by cell lines: Process of selection of lines and characterization of the cells. J. Immunol. 129:303–308.

    Google Scholar 

  47. Kuchroo, V. K., Sobel, R. A., Yamamura, T., Greenfield, E., Dorf, M. E., and Lees, M. B. 1991. Induction of experimental allergic encephalomyelitis by myelin proteolipid protein specific T cell clones and synthetic peptides. Pathobiology 59:305–312.

    Google Scholar 

  48. Whitham, R. H., Bourdette, D. N., Hashim, G. A., Herndon, R. M., Ilg, R. C., Vandenbark, A. A., and Offner, H. 1991. Lymphocytes from SJL/J mice immunized with spinal cord respond selectively to a peptide of proteolipid protein and transfer relapsing demyelinating EAE. J. Immunol. 146:101–107.

    Google Scholar 

  49. Tuohy, V. K., Lu, Z., Sobel, R. A., Laursen, R. A., and Lees, M. B. 1989. Identification of an encephalitogenic determinant of myelin proteolipid protein for SJL mice. J. Immunol. 142:1523–1527.

    Google Scholar 

  50. Adelmann, M., Wood, J., Benzel, I., Fiori, P., Lassmann, H., Matthieu, J. M., Gardinier, M. V., Dornmair, K., and Linington, C. 1995. The N-terminal domain of the myelin oligodendrocyte glycoprotein (MOG) induces acute demyelinating experimental autoimmune encephalomyelitis in the Lewis rat. J. Neuroimmunol. 63:17–27.

    Google Scholar 

  51. Hemmer, B., Fleckenstein, B. T., Vergelli, M., Jung, G., Mc-Farland, H., Martin, R., and Wiesmuller, K.-H. 1997. Identification of high potency microbial and self ligands for a human autoreactive class II-restricted T cell clone. J. Exp. Med. 185:1651–1659.

    Google Scholar 

  52. Ho, H. Z., Tiwari, J. L., Haile, R. W., Terasaki, P. I., and Morton, N. E. 1982. HLA-linked and unlinked determinants of multiple sclerosis. Immunogenetics 15:509–517.

    Google Scholar 

  53. Francis, D. A., Batchelor, J. R., McDonald, W. I., Hern, J. E. C., and Downie, A. W. 1986. Multiple sclerosis and HLADQwl. Lancet 1:211–214.

    Google Scholar 

  54. Kellar-Wood, H. F., Wood, N. W., Holmans, P., Clayton, D., Robertson, N., and Compston, D. A. S. 1995. Multiple sclerosis and the HLA-D region: linkage and association studies. J. Neuroimmunol. 58:183–190.

    Google Scholar 

  55. Hauser, S. L. 1995. T-cell receptor genes. Germline polymorphisms and genetic susceptibility to demyelinating diseases. Ann. NY Acad. Sci. 756:223–240.

    Google Scholar 

  56. Heber-Katz, E. and Acha-Orbea, H. 1989. The V-region disease hypothesis: Evidence from autoimmune encephalomyelitis. Immunol. Today 10:164–169.

    Google Scholar 

  57. Vandenbark, A. A., Hashim, G., and Offner, H. 1989. Immunization with a synthetic T-cell receptor V-region peptide protects against experimental autoimmune encephalomyelitis. Nature 341:541–544.

    Google Scholar 

  58. Offner, H., Hashim, G. A., and Vandenbark, A. A. 1991. T cell receptor peptide therapy triggers autoregulation of experimental encephalomyelitis. Science 251:430–432.

    Google Scholar 

  59. Kumar, V. and Sercarz, E. E. 1993. The involvement of T cell receptor peptide-specific regulatory CD4+ T cells in recovery from antigen-induced autoimmune disease. J. Exp. Med. 178:909–916.

    Google Scholar 

  60. Kumar, V., Coulsell, E., Ober, B., Hubbard, G., Sercarz, E., and Ward, E. S. 1997. Recombinant T cell receptor molecules can prevent and reverse experimental autoimmune encephalomyelitis. J. Immunol. 159:5150–5156.

    Google Scholar 

  61. Offner, H., Adlard, K., Bebo Jr., B. F., Schuster, J., Burrows, G. G., Buenafe, A. C., and Vandenbark, A. A. 1998. Vaccination with BV8S2 protein amplifies TCR specific regulation and protection against experimental autoimmune encephalomyelitis in TCR BV8S2 transgenic mice. J. Immunol. 161:2178–2186.

    Google Scholar 

  62. Rosloniec, E. F., Brand, D. D., Whittington, K. B., Stuart, J. M., Ciubotaru, M., and Ward, E. S. 1995. Vaccination with a recombinant Va domain of a TCR prevents the development of collagen-induced arthritis. J. Immunol. 155:4504–4511.

    Google Scholar 

  63. Vainiene, M., Celnik, B., Hashim, G. A., Vandenbark, A. A., and Offner, H. 1996. Natural immunodominant and EAE-protective determinants within the Lewis rat V 8.2 sequence include CDR2 and framework 3 idiotopes. J. Neurosci. Res. 43:137–145.

    Google Scholar 

  64. Kumar, V., Tabibiazar, R., Geysen, H. M., and Sercarz, E. 1995. Immunodominant framework region 3 peptide from TCR VB8.2 chain controls murine experimental autoimmune encephalomyelitis. J. Immunol. 154:1941–1950.

    Google Scholar 

  65. Broeren, C. P. M., Lucassen, M. A., Stipdonk, M. J. B., Zee, R., Boog, C. J. P., Kusters, J. G., and Eden, W. 1994. CDR1 T-cell receptor ß-chain peptide induces major histocompatibility complex class II-restricted T-T cell interactions. Proc. Natl. Acad. Sci. USA 91:5997–6001.

    Google Scholar 

  66. Hafler, D. A., Saadeh, M. G., Kuchroo, V. K., Milford, E., and Steinman, L. 1996. TCR usage in human and experimental demyelinating disease. Immunol. Today 17:152–159.

    Google Scholar 

  67. Ben-Nun, A., Liblau, R. S., Cohen, L., Lehmann, D., Tournier-Lasserve, E., Rosenzweig, A., Jingwu, Z., Raus, J. C. M., and Bach, M. A. 1991. Restricted T-cell receptor Vß gene usage by myelin basic protein-specific T-cell clones in multiple sclerosis: predominant genes vary in individuals. Proc. Natl. Acad. Sci. USA 88:2466–2470.

    Google Scholar 

  68. Oksenberg, J. R., Panzara, M. A., Begovich, A. B., Mitchell, D., Erlich, H. A., Murray, R. S., Shimonkevitz, R., Skerritt, M., Rothbard, J., and Bernard, C. C. A. 1993. Selection of T-cell receptor V-D-J gene rearrangements with specificity for a MBP peptide in brain lesions of MS. Nature 362:68–70.

    Google Scholar 

  69. Musette, P., Bequet, D., Delarbre, C., Gachelin, G., Kourilsky, P., and Dormont, D. 1996. Expansion of a recurrent VB5.3+ Tcell population in newly diagnosed and untreated HLA-DR2 multiple sclerosis patients. Proc. Natl. Acad. Sci. USA 93:12461–12466.

    Google Scholar 

  70. Shimonkevitz, R., Murray, R., and Kotzin, B. 1995. Characterization of T-cell receptor Vß usage in the brain of a subject with multiple sclerosis. Ann. NY Acad. Sci. 756:305–306.

    Google Scholar 

  71. Afshar, G., Muraro, P. A., McFarland, H. F., and Martin, R. 1998. Lack of over-expression of T cell receptor VB5.2 in myelin basic protein-specific T cell lines derived from HLADR2 positive multiple sclerosis patients and controls. J. Neuroimmunol. 84:7–13.

    Google Scholar 

  72. Antel, J. P., Arnason, B. G., and Medof, M. E. 1979. Suppressor cell function in multiple sclerosis: correlation with clinical disease activity. Ann. Neurol. 5:338–342.

    Google Scholar 

  73. Antel, J. P., Bania, M. B., Reder, A., and Cashman, N. 1986. Activated suppressor cell dysfunction in progressive multiple sclerosis. J. lmmunol. 137:137–141.

    Google Scholar 

  74. Antel, J. P., Nicholas, M. K., Bania, M. B., Reder, A. T., Arnason, B. G., and Joseph, L. 1986. Comparison of T8+ cell-mediated suppressor and cytotoxic functions in multiple sclerosis. J. Neuroimmunol. 12:215–224.

    Google Scholar 

  75. Antel, J., Bania, M., Noronha, A., and Neely, S. 1986. Defective suppressor cell function mediated by T8+ cell lines from patients with progressive multiple sclerosis. J. Immunol. 137:3436–3439.

    Google Scholar 

  76. Antel, J., Brown, M., Nicholas, M. K., Blain, M., Noronha, A., and Reder, A. 1988. Activated suppressor cell function in multiple sclerosis-clinical correlations. J. Neuroimmunol. 17:323–330.

    Google Scholar 

  77. Vandenbark, A. A., Finn, T., Offner, H., Whitham, R., and Bourdette, D. N. 2000. Diminished frequency of IL-10 secreting TCR BV5S2 peptide-reactive T cells in MS. In Immunology 2000. Seattle, Washington: Federation of American Societies for Experimental Biology A1218.

    Google Scholar 

  78. Bourdette, D. N., Whitham, R. H., Chou, Y. K., Morrison, W. J., Atherton, J., Kenny, C., Liefeld, D., Hashim, G. A., Offner, H., and Vandenbark, A. A. 1994. Immunity to T cell receptor peptides in multiple sclerosis. I. Successful immunization of patients with synthetic Vβ5.2 and Vβ6.1 CDR2 peptides. J. Immunol. 152:2510–2519.

    Google Scholar 

  79. Bourdette, D. N., Chou, Y. K., Whitham, R. H., Buckner, J., Kwon, H. J., Nepom, G. T., Buenafe, A., Cooper, S. A., Allegretta, M., Hashim, G. A., Offner, H., and Vandenbark, A. A. 1998. Immunity to T cell receptor peptides in multiple sclerosis. III. Preferential immunogenicity of complementarity determining region 2 peptides from disease-associated T cell receptor BV genes. J. Immunol. 161:1034–1044.

    Google Scholar 

  80. Gold, D. P., Smith, R. A., Golding, A. B., Morgan, E. E., Dafashy, T., Nelson, J., Smith, L., Diveley, J., Laxer, J. A., Richieri, S. P., Carlo, D. J., Brostoff, S. W., and Wilson, D. B. 1997. Results of a phase I clinical trial of a T-cell receptor vaccine in patients with multiple sclerosis. II. Comparative analysis of TCR utilization in CSF T-cell populations before and after vaccination with a TCRVß6 CDR2 peptide. J. Neuroimmunol. 76:29.

    Google Scholar 

  81. Hong, J., Zang, Y., Tejada-Simon, M. V., Li, S., Singh, R., Yang, D., Rivera, V. M., Killian, J. M., and Zhang, J. 1999. A common T cell receptor V-D-J-sequence in VB13.1 T cells recognizing an immunodominant peptide of myelin basic protein in multiple sclerosis. J. lmmunol. 163:3530.

    Google Scholar 

  82. Harris, E. D. 1990. Rheumatoid arthritis: Pathophysiology and implications for therapy. New England J. Med. 322:1277–1289.

    Google Scholar 

  83. Koopman, W. J. and Gay, S. 1993. Do nonimmunologically mediated pathways play a role in the pathogenesis of rheumatoid arthritis? Rheum. Dis. Clin. North Am. 19:107–122.

    Google Scholar 

  84. Nepom, G. T. and Erlich, H. 1991. MHC class II molecules and autoimmunity. Ann. Rev. Immunol. 9:493–525.

    Google Scholar 

  85. Winchester, R. 1994. The molecular basis of susceptibility to rheumatoid arthritis. Adv. Immunol. 56:389–466.

    Google Scholar 

  86. Kinne, R. W., Palombo-Kinne, E., and Emmrich, F. 1997. T-cells in the pathogenesis of rheumatoid arthritis: villains or accomplices. Biochem. Biophys. Acta 1360:109–141.

    Google Scholar 

  87. Fox, D. A. 1997. The role of T cells in the immunopathogenesis of rheumatoid arthritis: new perspectives. Arthritis Rheum. 40:598–609.

    Google Scholar 

  88. Falta, M. T. and Kotzin, B. L. 1998. T cells as primary players in rheumatoid arthritis. Pages 201–231, in Miossec, P., van den Berg, W., and Firestein, G. S. (eds.), T Cells in Arthritis. Birkhauser Verlag, Basel.

    Google Scholar 

  89. Paliard, X., West, S. G., Lafferty, J., Clements, J. R., Kappler, J. W., and Marrack, P. 1991. Evidence for the effects of a superantigen in rheumatoid arthritis. Science 253:325–329.

    Google Scholar 

  90. Howell, M. D., Diveley, J. P., Lundeen, K. A., Esty, A., Winters, S. T., Carlo, D. J., and Brostoff, S. W. 1991. Limited T-cell receptor ß-chain heterogeneity among interleukin 2 receptor-positive synovialTcells suggests a role for superantigen in rheumatoid arthritis. Proc. Natl. Acad. Sci. USA 88:10921–10925.

    Google Scholar 

  91. Choi, Y., Herman, A., DiGiusto, D., Wade, T., Marrack, P., and Kappler, J. 1990. Residues of the variable region of the T-cell receptor β-chain that interact with S. aureus toxin superantigens. Nature 346:471–473.

    Google Scholar 

  92. Pullen, A. M., Wade, T., Marrack, P., and Kappler, J. 1990. Identification of the region of T cell receptor β chain that interacts with the self-superantigen Mls-1+. Cell 61:1365–1374.

    Google Scholar 

  93. Moreland, L. W., Heck, L. W., and Koopman, W. J. 1997. Biologic agents for treating rheumatoid arthritis: concepts and progress. Arthritis Rheum. 40:397–409.

    Google Scholar 

  94. Kotzin, B. L. and Kappler, J. 1998. Editorial: Targeting the T cell receptor in rheumatoid arthritis. Arthritis Rheum. 41:1906–1910.

    Google Scholar 

  95. VanderBorght, A., Geusens, P., Vandevyver, C., Raus, J., and Stinissen, P. 2000. Skewed T-cell receptor variable gene usage in the synovium of early and chronic rheumatoid arthritis patients and persistence of clonally expanded T cells in a chronic patient. Rheumatology 39:1189–1201.

    Google Scholar 

  96. Zagon, G., Tumang, J. R., Li, Y., Friedman, S. M., and Crow, M. K. 1994. Increased frequency of Vβ 17-positive T cells in patients with rheumatoid arthritis. Arthritis Rheum. 37:1431–1440.

    Google Scholar 

  97. Moreland, L. W., Heck, L. W., Koopman, W. J., Saway, A., Adamson, T. C., Fronek, Z., O'Connor, R. D., Morgan, E. E., Diveley, J. P., and Richieri, S. P. 1996. Vβ17 T cell receptor peptide vaccination in rheumatoid arthritis: Results of a phase I dose escalation study. J. Rheumatol. 23:1353–1362.

    Google Scholar 

  98. Moreland, L. W., Morgan, E. E., Adamson, T. C., Fronek, Z., Calabrese, L. H., Cash, J. M., Markenson, J. A., Matsumoto, A. K., Bathon, J., Matteson, E. L., et al. 1998. T cell receptor peptide vaccination in rheumatoid arthritis. A placebo-controlled trial using a combination of Vβ3, Vβ14, and Vβ17 peptides. Arthritis Rheum. 41:1919–1929.

    Google Scholar 

  99. Norris, D. A., Travers, J. D., and Leung, Y. M. 1997. Lymphocyte activation in the pathogenesis of psoriasis. J. Invest. Dermatol. 109:1–4.

    Google Scholar 

  100. Boehncke, W.-H., Dressel, D., Zollner, T. M., and Kaufmann, R. 1996. Pulling the trigger on psoriasis. Nature 379:777.

    Google Scholar 

  101. Wrone-Smith, T. and Nickoloff, B. J. 1996. Dermal injection of immunocytes induces psoriasis. J. Clin. Invest. 98:1878–1887.

    Google Scholar 

  102. Chang, C. C., Smith, L. R., and Froning, K. J. 1994. CD8+ T cells in psoriatic lesions preferentially use T cell receptors Vβ3 and/or Vβ13.1 genes. Proc. Natl. Acad. Sci. USA 91:9282–9286.

    Google Scholar 

  103. Chang, C. C., Smith, L. R., and Froning, K. J. 1995. CD8+ T-cells in psoriatic lesions preferentially use T-cell receptors Vβ3 and/or Vβ13.1 genes. Ann. NY Acad. Sci. 756:370–381.

    Google Scholar 

  104. Gottlieb, S. L., Gilleaudeau, P., Johnson, R., Estes, L., Woodworth, T. G., Gottlieb, A. B., and Krueger, R. 1995. Response of psoriasis to a lymphocyte-selective toxin (DAB389IL-2) suggests a primary immune, but not keratinocyte, pathogenic basis. Nature Med. 1:442–447.

    Google Scholar 

  105. Vallat, V. P., Gilleaudeau, P., Battat, L., Wolfe, J., Nabeya, R., Heftler, N., Hodak, E., Gottlieb, A. B., and Krueger, J. G. 1994. PUVA bath therapy strongly suppresses immunological and epidermal activation in psoriasis: a possible cellular basis for remittive therapy. J. Exp. Med. 180:283–296.

    Google Scholar 

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Authors and Affiliations

  1. Neuroimmunology Research, Veterans Affairs Medical Center, Portland, OR

    Arthur A. Vandenbark, Dennis Bourdette, Ruth Whitham & Halina Offner

  2. Department of Neurology, Oregon Health Sciences University, Portland, OR

    Arthur A. Vandenbark, Dennis Bourdette, Ruth Whitham & Halina Offner

  3. Department of Microbiology and Immunology, Oregon Health Sciences University, Portland, OR

    Arthur A. Vandenbark

  4. The Immune Response Corporation, Carlsbad, CA

    Elizabeth Morgan, Richard Bartholomew & Dennis Carlo

  5. Favrile, Inc., San Diego, CA

    Daniel Gold

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  1. Arthur A. Vandenbark
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Vandenbark, A.A., Morgan, E., Bartholomew, R. et al. TCR Peptide Therapy in Human Autoimmune Diseases. Neurochem Res 26, 713–730 (2001). https://doi.org/10.1023/A:1010951706830

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